The systemic availability of testosterone (Te) in healthy men declines by 35-50% by age 75 compared with age 25 yr. Illness, trauma, surgery, inanition, pain, stress, medications and institutionalization further reduce Te availability in elderly subjects. However, the primary cause of progressive age-related androgen depletion is not known. The issue is significant, because impoverished anabolism accentuates physical frailty, exacerbates comorbidity, reduces quality of life and expands health-care costs. Studies accomplished to date suggest that multiple (rather than single) mechanisms mediate Te depletion in older men, viz.: (i) decreased release of hypothalamic gonadotropin-releasing hormone (GnRH), which drives pituitary luteinizing hormone (LH) secretion; (ii) impaired Leydig-cell responsiveness to LH pulses; and reduced feedback by Te onto GnRH and LH secretion. The last issue is central to understanding how aging disrupts the male GnRH-LH-Te axis, because the axis operates as a counterbalanced feedforward and feedback system. Accordingly, the first major objective of this proposal is to determine the basis of feedback failure using a novel clinical paradigm and analytical methodology just developed under R21 AG23777-02. Hypothesis I. Age disrupts androgen and estrogen receptor-mediated negative feedback on GnRH outflow and/or pituitary LH secretion, as quantified under a selective hypothalamic vis--vis pituitary feedback clamp. In addition to the age-associated decline in Te availability, superimposed acute illness and chronic disease further suppress the GnRH-LH-Te axis at any age. The mechanisms mediating inhibitory effects are unknown. Stress concomitantly alters the anabolic GH-IGF-I and catabolic ACTH-cortisol axes. These observations raise the question, How does aging impact stress adaptations among all 3 of Te, GH and cortisol? This fundamental issue will be addressed under the second major objective, stated as a hypothesis. Hypothesis II. Experimentally controlled metabolic, inflammatory and lifestyle (sleep-deprivation) stressors will inhibit GnRH-LH-Te secretion to a greater extent in older than young men, and unmask concomitant age-related failure of stress adaptations of the GH-IGF-I and ACTH-cortisol axes. Unraveling the bases of androgen depletion in the aging male should spark new preventive strategies to obviate failure of anabolic drive, and thus preserve quality of life and function in older individuals. PUBLIC HEALTH RELEVANCE: Aging results in thinner bones, weaker muscles, more abdominal fat, higher blood glucose, greater risk of a heart attack, reduced sexual energy, forgetfulness and increased medical disability. Certain outcomes are related to lower male sex hormones, which fall by about 50% between the ages of 25 and 75 years. Why or how the decline occurs is not known. This grant studies mechanisms in the brain, pituitary (master) gland and testis (male gonad), which begin to fail in aging men under stress.